The present invention relates to a novel process for the preparation of 4-chlorobiphenyls from haloaromatics and aryl Grignard reagents using a phosphinopalladium ferrocene catalyst. 4-Chlorobiphenyls are of industrial importance as active compound precursors for matrix metalloprotease inhibitors.
A frequently used method for the synthesis of 4-chlorobiphenyls on the laboratory scale is palladium-catalyzed cross-coupling, in which iodine and bromoaromatics are reacted with organometallic aryl derivatives, in particular arylboronic acids or aryl Grignard reagents, in the presence of palladium or nickel catalysts. Examples which describe this methodology are found, for example, in Y. Ikoma et al., Synthetic Commun. 21 (1991), 3,481-487.
Despite the large number of publications in the field of the synthesis of 4-chlorobiphenyls in the presence of nickel or palladium catalysts, to date no 25 examples of a relatively large industrial transposition of the methods are known. This is to be attributed to the fact that the catalyst systems described can frequently only be employed with uneconomical amounts of catalysts or low selectivities, i.e. high rates of dimerization products and dechlorinated products (A. Hutz et al., Tetrahedron, 45, 21, 1989, 6679-6682). Otherwise, large amounts of catalyst--generally &gt;1 mol %--must be added in order to achieve industrially utilizable conversions. On account of the complexity of the reaction mixtures, simple recycling of catalyst is moreover not possible, so that catalyst costs as a rule prevent industrial realization.
Moreover, aryl transfers are observed as a side reaction in the Suzuki coupling of substituted biphenyls using customary catalyst systems, such as Pd(OAc).sub.2 /triphenylphosphane mixtures (O'Keefe et al., Tetrahedron Letters 1992, 6679).